The objectives of this research proposal are to study vitamin D-pancreas interrelationships. The calcium homeostatic actions of vitamin D in higher animals are now known to be mediated through the actions of its daughter metabolites 1,25-dihydroxyvitamin D (1,25(OH)2D3) and possible 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). In vitamin D responsive tissues, e.g., the intestine, bone, and kidney, 1,25(OH)2D3 is known to interact with a tissue specific, high affinity receptor protein, forming a steroid-receptor complex. After translocation to the cell nucleus and activation of gene transcription new proteins are biosynthesized - including a vitamin D-dependent calcium binding protein (CaBP). Alloxan-diabetes in the rat has been previously shown to impair intestinal levels of CaBP and intestinal calcium absorption. Recently the Principal Investigator has found that the pancreas is also a target tissue for 1,25(OH)2D3. Chick pancreas contains a high affinity receptor for 1,25(OH)2D3 as well as substantial quantities of the vitamin D-dependent CaBP. In addition, vitamin D deficiency in the rat was found to impair by 50% the secretion of insulin but not glucagon as determined by studies on the isolated perfused rat pancreas. The proposed projects include: (a) a study of vitamin D metabolism in alloxan or streptozotocin induced diabetes (rats) or hereditary diabetes in the presence and absence of replacement insulin; (b) biochemical characterization of pancreatic receptors for 1,25(OH)2D3 in mammalian systems (rat, mouse, dog, primate); and (c) a detailed evaluation of the effect of vitamin D, 1,25(OH)2D3 and 24,25(OH)2D3 in D-deficient rats on affecting insulin and glucagon secretion in the isolated perfused rat pancreas. Such studies will clarify vitamin D-pancreatic relationships and may provide the basis for understanding the etiology of the well documented reduced bone mass (osteoporosis, osteopenia) in subjects with diabetes mellitus and impaired release of insulin in subjects with hypoparathyroidism.